The aim of this proposal is to test directly in the mouse brain an old and widely believed idea that excess calcium entering a neuron through glutamate receptors can cause neurodegenerative brain disease as is observed in Alzheimer's patients. This will be accomplished by genetic engineering mice so that they express glutamate receptors which flux abnormally high amounts of calcium into the cell during normal synaptic transmission. The experiments will make use of recombinant DNA technology and the production of mutant mice by genetic engineering methods. Gene targeting methods will be used to knockout or disrupt glutamate receptor genes. Point mutations will be introduced into glutamate receptor genes using the recently developed "Hit and Run" technology. The mutant mice will be analyzed using a variety of techniques. The brains will be sectioned and examined for gross morphology changes and evidence of cell death. The slice preparation will be used to measure synaptic transmission and the ability of the synapses to undergo synaptic plasticity phenomenon such as LTP and LDP. The Morris maze will be used to test for learning and memory function.